Download Phytochemistry and Pharmacological Properties of Centella asiatica

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Current Updates on Centella asiatica: Phytochemistry, Pharmacology and Traditional uses
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Dipankar Chandra Roy, Shital Kumar Barman, Md. Munan Shaik*
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Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia-7003,
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Bangladesh.
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*Corresponding author, [email protected] and [email protected]
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Md. Munan Shaik, Ph. D
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ABSTRACT
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Plants have been demonstrated extraordinary source of medicine, and recently focus on
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medicinal plant research has increased. Centella asiatica is well known for its traditional uses
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and medicinal properties for the treatment of many diseases. The published literatures mention
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the use of this plant as whole and bioactive compounds isolated are widely used in the treatment
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of various human ailments. C. asiatica reported to possess various pharmacological activities:
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antimicrobial activity, anticancer activity, wound healing activity, neuroprotechtive activity,
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immunomodulatory activity, anti-inflammatory activity, hepatoprotective activity, insecticidal
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activity, and antioxidant activity. C. asiatica is also rich in flavonoids and terpenoids compounds
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among them asiatic acid, asiaticoside, madecassoside is well characterized for its
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pharmacological value. The present review summarized widespread information on
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phytochemistry, isolated and characterized bioactive compounds, pharmacological properties, in
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vitro propagation and traditional uses of the important medicinal plant C. asiatica.
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Keywords: Centella asiatica, Medicinal Plants, Triterpenes, Terpenoids Phytochemistry,
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Pharmacology, Neuroprotechtive activity, Wound Healing actitivty, Anti-inflammatory activity,
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Anticancer activity.
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Introduction
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Medicinal plants are an important episode in the medical sector. Around 5000 species have
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specific therapeutic value among 2,50,000 higher plant species on earth (Joy et al., 1998).
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Centella asiatica has a long history in ancient Ayurvedic remedy, used in wound healing,
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cleansing for skin problem and digestive disorders (Chevallier, 2001) and effective in treatment
1
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of stomach ulcers, mental fatigue, diarrhea, epilepsy, hepatitis, syphilis and asthma (Goldstein
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and Goldstein, 2012). Such traditional uses and reputation of this species cross over the boundary
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limit of Bangladesh, India, and Srilanka and now extensively used in the West (Chevallier, 2001;
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Meulenbeld and Wujastyk, 2001). C. asiatica and Hydrocotyle asiatica, belongs to family
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Apiaceae (Umbelliferae) are used synonymously and commonly known as Thankuni (Bengali),
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Bemgsag/ Brahma-Manduki/Gotukola/Khulakhudi/Mandookaparni (Hindi), Indian Pennywort/
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Marsh Pennywort/ Gotu kola (English) (Singh et al., 2010). C. asiatica is creeping, perennial
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herb with up to 2m long slender and tender horizontal reddish prostrate stolons, characterized by
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long rooting internodes (Jamil et al., 2007; Koh et al., 2009). Glabrous leaves, 1-3 arising from
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each node of the stems, are green, fan-shaped or round renifrom, 1.4 cm by 1.7 cm with crenate
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or dentate margin (Jamil et al., 2007; Koh et al., 2009). Flowers occurring in July-September are
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umbels with 3-4 white or light purple-to-pink petals bearing 4mm long oval to globular shaped
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fruit (Chauhan, 1999; Jamil et al., 2007; Koh et al., 2009). The most used part for medicinal
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purposes is dried whole plant, leaves and stems. C. asiatica plant is indigenous to Bangladesh,
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India, West Pakistan, China, Japan, America and the pacific (Koh et al., 2009). This plant is
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commonly seen in moist, sandy or clayey soils waste places (Jamil et al., 2007).
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Phytochemistry
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C. asiatica is a rich source of amino acids, flavonoids, terpenoids, essential oils, alkaloids etc.
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(Table 1). Most of the phytochemical studies concentrated on leaves and the constituents vary
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depending upon the geographical distribution (Chong NJ and Aziz, 2011).
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Table 1: Chemical constituents of C. asiatica
Main groups
Constituents
References
Amino acids
Alanine and serine (major components), aminobutyrate, aspartate, glutamate,
(Barnes et
histidine, lysine, threonine, arginine, leucine, iso-leucine, valine, methionine,
al., 2007;
tyrosine, phenylalanine, proline, cystine, glycine.
Chong NJ
and Aziz,
2011),
Carbohydrates
Glucose, mesoinositol, centellose, pectin, arabinogalactan
(Chong NJ
and Aziz,
2011)
2
Phenols
Flavonoids: Kaempferol, kaempferol-3-o-β-d-glucuronide, castilliferol,
(Bhandari
quercetin, quercetin-3-o-β-d-glucuronide, castillicetin, apigenin, rutin, luteolin,
et al., 2007;
naringin
Zheng and
Qin, 2007;
Chong NJ
and Aziz,
2011)
Phenylpropanoids: Rosmarinic acid, chlorogenic acid, 3,4-di-o-caffeoyl quinic
(Chong NJ
acid, 1,5-di-o-caffeoyl quinic acid, 3,5-di-o-caffeoyl quinic acid, 4,5-di-o-
and Aziz,
caffeoyl quinic acid, isochlorogenic acid
2011)
Tannin: Tannin, phlobatannin
(Chong NJ
and Aziz,
2011)
Terpenoids
Triterpenes, asiaticoside, centelloside, madecassoside, brahmoside,
(Barnes et
brahminoside (saponin glycosides), asiaticentoic acid, centellic acid, centoic
al., 2007;
acid, madecassic acid, terminolic acid and betulic acid.
Jamil et al.,
2007)
Volatile oils
Various terpenoids: β-caryophyllene, trans β-farnesene and germacrene D
(Barnes et
and fatty oils
(sesquiterpenes), α-pinene and β-pinene.
al., 2007;
Fatty acids: linoleic acid, linolenic acid, lignocene, oleic acid, palmitic acid,
Jamil et al.,
stearic acid.
2007)
Ascorbic acid, nicotinic acid, β-carotene
(Chong NJ
Vitamins
and Aziz,
2011)
Mineral
Calcium, phosphorus, iron, potassium, magnesium, manganese, zinc, sodium,
(Chong NJ
copper
and Aziz,
2011)
Other
Hydrocotylin (an alkaloid), vallerine (a bitter principle), phytosterols (e.g.
(Barnes et
constituents
campesterol, sitosterol, stigmasterol), resin. ~14 different polyacetylenes (8-
al., 2007;
acetoxycentellynol, cadiyenol, dotriacont-8-en-1-oic acid, 11-oxoheneicosanyl
Chong NJ
cyclohexane).
and Aziz,
2011)
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Bioactive compounds
3
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C. asiatica is being used as a natural source of medicine for long time. The main active
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constitients of C. asitica are pentacyclic triterpenes (asiatic acid, madecassic acid, asiaticoside,
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and madecassoside, etc.) (Puttarak and Panichayupakaranant, 2012b). Two new dammarane
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monodesmosides centellosides A (1) and B (2), and two new natural products ginsenosides Mc
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(10) and Y (11), were reported recently (Weng et al., 2011; Han et al., 2012). An efficient
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microwave-assisted extraction method was developed for asiatic acid and a sensitive method for
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quantification of it and madecassoside in rat plasma also reported (Han et al., 2012; Nasir et al.,
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2012; Puttarak and Panichayupakaranant, 2012a). Asiatic acid has shown numerous therapeutic
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activities and biotransformation of it by Penicillium lilacinum ACCC 31890, Fusarium equiseti
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CGMCC 3.3658, and Streptomyces griseus CGMCC 4.18 strains was investigated and structure
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were deduced for all new derivaties (Guo et al., 2012). The ELISA method was investigated as
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an analytical tool for quality control and standardization of pharmaceutical products containing
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asiaticoside and madecassoside (Juengwatanatrakul et al., 2011; Tassanawat et al., 2012).
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Bioactive compounds isolated and characterized from C. asiatica are summarized in Table 2
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with their physical properties.
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Table 2: Structure and biological activities of bioactive compounds isolated from C. asiatica.
Name of the
Structure
Biological activity
compounds
Referenc
es
Asiatic acid
Aids in generation of neuroglia; promotes
(Huang et
(C30H48O5;
wound healing, promotes cuticle
al., 2011;
mw = 488.71)
cornification; stimulates granulation; induces
Nasir et
gene expression changes, enhancing learning
al., 2011a,
and memory properties, antinociceptive
2012;
activity, anti-inflammation activity,
Zhou et
acetylcholinesterase inhibitory activity, anti
al., 2011;
apoptotic activity
Song et
al., 2012;
Zhang et
al., 2012)
4
Asiaticoside
Anti-inflammatory; antioxidant induces gene
(Tang et
(C48H78O19;
expression changes, wound healing, reduces
al., 2011a;
mw = 959.15)
scar formation, neuroprotective activity,
Zhou et
improve collagen biosynthesis
al., 2011;
Lee et al.,
2012;
Nowwarot
e et al.,
2012;
Paolino et
al., 2012;
Wan et
al., 2012;
Xu et al.,
2012a)
Madecassic acid
Induces gene expression changes,
(Zhou et
(C30H48O6;
al., 2011;
mw = 504.71)
Song et
al., 2012)
Madecassoside
Induces gene expression changes, protection
(Zhou et
(C48H78O20;
of endothelial cells from oxidative injury.
al., 2011;
mw = 975.14)
Bian et
al., 2012)
Quercetin
Anti-HIV-1, antiasthmatic, antibacterial,
(Chong
(C15H10O7;
antihepatotoxin, antihypertensive, anti-
NJ and
mw = 302.24)
inflammatory, antitussive, antiviral, coronary
Aziz,
vasodilator, antihypercholesterolemic, 5-HT
2011;
inhibitor, smooth muscle relaxant, platelet
Zhou et
aggregation inhibitor, 3’,5’-cAMP-
al., 2011)
phosphodiesterase inhibitor, fatty acid
synthetase inhibitor, aldose reductase
inhibitor (eye lens), protein kinase C
inhibitor; antihypertensive, reduces blood
capillary brittleness, antioxidant
5
Kaempferol
Anti-HIV-1, antibacterial; anti-
(Chong
(C15H10O6;
inflammatory, antitussive to cure trachitis,
NJ and
mw = 286.24)
antioxidant, ∆5 -lipoxygenase inhibitor;
Aziz,
iodinate thyronine deiodinase inhibitor;
2011;
aldose reductase inhibitor
Zhou et
al., 2011)
Apigenin
Antibacterial, antiulcerative, antispasmodic
(Bhandari
(C15H10O5; mw =
(smooth muscle), diuretic, aldose reductase
et al.,
270.24)
inhibitor, antihypertensive, anti-
2007;
inflammatory, antioxidant, nodulation signal
Zhou et
for metabiosis of pea and Rhizobium
al., 2011)
leguminosarum,
Rutin (C27H30O16;
Anti-inflammatory, antiviral, aldose
(Bhandari
mw = 610.53)
reductase Inhibitor, insect antifeedant
et al.,
(Heliothis zea), insect phagostimulant
2007;
(Gastrophysa atrocynea), antioxidant,
Zhou et
inhibits cancer cell invasion, reduces blood
al., 2011)
capillary permeability and brittleness
Luteolin (C15H10O6;
Antiallergic, antibacterial, antifungal,
(Bhandari
mw = 286.24)
cytotoxic, anti-inflammatory, antispasmodic,
et al.,
antitussive, antiviral, enhances arterial
2007;
tension and lowers intravenous tension,
Zhou et
enhances blood capillary permeability,
al., 2011)
immunoenhancer, increases coronary flow;
dihydrocoenzyme I (NADH) oxidase
inhibitor, iodine-induced thyronine
deiodinase inhibitor, aldose reductase
inhibitor, anti-inflammatory, anti-HIV
activity
Quercitrin
Antibacterial, antineoplastic,
(Bhandari
(C21H20O11;
antihepatotoxin, anti-inflammatory,
et al.,
mw = 448.39)
antimutagenic, antiviral, diuretic,
2007;
Hemostatic, aldose reductase inhibitor,
Zhou et
antioxidant, insect antifeedant (Bombyx
al., 2011)
mor), insect phagostimulant (Gastrophysa
atriocyaea), hepatoprotective
6
Naringin
Antibacterial, anti-inflammatory, antiviral,
(Zheng
(C27H32O14;
aldose reductase inhibitor, passive cutaneous
and Qin,
mw = 580.55)
anaphylaxis inhibitor
2007;
Zhou et
al., 2011)
Betulic acid
Antineoplastic, cytotoxic, antitubercular,
(Jamil et
(C30H48O3;
antibacterial
al., 2007;
Mw = 456.72)
Zhou et
al., 2011)
α-Pinene (C10H16;
Antifungal, antitussive, irritant.
mw = 136.24;
(Barnes et
al., 2007;
Zhou et
al., 2011)
β-Pinene (C10H16;
Antifungal, anti-inflammatory, antitussive
mw = 136.24;
(Barnes et
al., 2007;
Zhou et
al., 2011)
Β-caryophyllene
Flavorant
(Barnes et
(C15H24;
al., 2007;
mw= 204.36);
Zhou et
al., 2011)
Linolenic acid
Nutrient, inhibits cancer cell invasion, 5α-
(Jamil et
(C18H30O2;
reductase inhibitor
al., 2007;
mw = 278.44)
Zhou et
al., 2011)
Oleic acid
Increases absorption through skin,
(Jamil et
(C18H34O2;
dermatitis, inhibits cancer cell invasion
al., 2007;
mw = 282.47)
Zhou et
al., 2011)
Stigmasterol
Antihypercholesterolemic, antimutagenic,
(Barnes et
(C29H48O;
cytotoxic inactive, antileishmanial,
al., 2007;
mw = 412.71)
antimalarial, antitrypanosomal, platelet
Zhou et
aggregation inhibitor, antiviral
al., 2011)
Ascorbic acid
Antioxidant, antibacterial, anti-infective,
(Chong
(C6H8O6;
antidote, antihypercholesterolemic, inhibits
NJ and
mw = 176.13)
production of Carcinogen, induces tissue to
Aziz,
produce collagen, hematopoietic activity
2011;
7
Zhou et
al., 2011)
Nicotinic acid
Antihypercholesterolemic, vasodilator
(Chong
(C6H5NO2;
(peripheral)
NJ and
mw = 123.11)
Aziz,
2011;
Zhou et
al., 2011)
β-Carotene (C40H56;
EBV-EA activation inhibitor, anti-tumor
(Chong
mw = 536.89)
promoter, ultraviolet screen, pigment, food
NJ and
additive
Aziz,
2011;
Zhou et
al., 2011)
Alanine (C3H7NO2;
Food additive, reverses glucopenia and
(Barnes et
mw = 89.09)
ketosis caused by starvation, glucagon
al., 2007;
secretion promotor
Zhou et
al., 2011)
Chlorogenic acid
Antioxidant, antineoplastic, cytotoxic,
(Chong
(C16H18O9; mw =
antimutagenic, antiviral, choleretic,
NJ and
354.32)
hemostatic, leukopoietic, antimalarial,
Aziz,
2011;
Zhou et
al., 2011)
Irbic acid
(C28H26O15; mw =
Strong radical scavenging, collagenase
(Antogno
inhibitory activity
ni et al.,
2011)
602)
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Pharmacological Activity
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The primary constituents of C. asiatica is the triterpenic fractions which showed wide range of
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defensive and therapeutic effects, most prominently influencing of collagen production and
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deposition in wound healing. Titrated Extract of Centella asiatica (TECA) is used to treat several
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microcirculatory problems, skin inflammation (eczema, atopic dermatitis, leprosy, varicose
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ulcers, etc.) fever, intestinal problems and genitourinary conditions (Belcaro et al., 2011). C.
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asiatica exerts diverse pharmacological activities such as antibacterial, antidepresent, antiemetic,
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antineoplastic, antioxidant, antithrombotic, anxiolytic, gastroprotective, immunomodulatory,
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antigenotoxic, nerve regenerative, reproductive, wound healing etc. due to the presence of
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several saponin constituents, including asiaticoside, asiatic acid, madecassic acid and some other
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bioactive compounds (Craker and Simon, 1986; Koh et al., 2009; Kim et al., 2011).
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Anti-inflammatory activity: Asiatic acid and madecassic acid showed anti-inflammatory effect
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by the inhibition of enzymes (iNOS, cyclooxygenase-2 (COX-2)), interleukins (IL-6, IL-1β),
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cytokine tumor necrosis factor (TNF-α) expression through the down-regulation of NF-κB
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activation in lipopolysaccharide (LPS) induced RAW 264.7 murine macrophage cells (Yun et al.,
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2008; Won et al., 2010). Madecassoside prevented collagen II (CII)-induced arthritis (CIA) in
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mice (Liu et al., 2008). Ethanolic extract of C. aiatica at dose 100mg/kg of body weight showed
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anti-inflammatory activity in rats similar to standard Ibuprofen (George et al., 2009). 3,5-
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dicaffeoyl-4-malonylquinic acid, extract from C. asiatica demonstrated beneficial effect on
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inflammatory bowel disease in rats (Di Paola et al., 2010). In experimental animal asiaticoside
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dose inhibited LPS induced fever and inflammatory response, including serum TNF-α and IL-6
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production, liver myeloperoxidase (MPO) activity, brain COX-2 protein expression and
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prostaglandin E(2) (PGE(2) ) production (Wan et al., 2012). Asiaticoside G was also reported
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having anti-inflammatory property in LPS-stimulated RAW 264.7 cells (Nhiem et al., 2011).
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Anticancer activity: A large number of experimental reports proved that different solvent
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extracts of C. asiatica has anti-cancerous activity. In vitro study on HeLa, HepG2, SW480 and
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MCF-7 cell lines showed that methanolic extract had induced apoptosis in human breast
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cancerous MCF-7 cells (Babykutty et al., 2009). Water extracts induced apoptosis in colonic
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crypts and exerted chemopreventive effect on colon tumorigenesis in male F344 rats (Bunpo et
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al., 2004). Asiatic acid induced apoptosis in human melanoma SK-MEL-2 cells (responsible for
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skin cancer) and SW480 human colon cancer cells (Park et al., 2005; Tang et al., 2009).
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Asiaticoside enhanced anti-tumor activity of vincristine in cancer cells (Huang et al., 2004).
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Constituents in the methanol extract inhibited the proliferation of human gastric adenocarcinoma
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(MK-1), human uterine carcinoma (HeLa), and murine melanoma (B16F10) cells (Yoshida et al.,
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2005).
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Anticonvulsant activity: Oral administration of different extracts from C. asiatica for 1 week at a
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dose of 200mg/kg of body weight of in pentylenetetrazol (induces seizure) induced rats increased
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the level of acetylcholine (neurotransmitter) and decreased the activity of acetylcholinesterase,
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causes perceptible changes in the cholinergic system which indicates the anticonvulsant activity
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(Visweswari et al., 2010).
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Antidepressant activity: Total triterpenes from C. asiatica showed reduced immobility time and
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ameliorating the imbalance of amino acid levels in forced swimming mice indicate
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antidepressant activity (Chen et al., 2003). Total triterpenes from C. asiatica also ameliorated the
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function of hypothalamic-pituitary-adrenal axis (HPA axis), increased the contents of
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monoamine neurotransmitters in rat brain and reduced the corticosterone level in serum (Chen et
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al., 2005).
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Antioxidant activity: C. asiatica possesses potent antioxidant activity, which can exerted
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neuroprotective effect and effect against age related oxidative damage in rats brain (Subathra et
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al., 2005). The anti-oxidant enzymes, like superoxide dismutase (SOD), catalase and glutathione
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peroxidase (GSHPx) were significantly increased, and anti-oxidants like glutathione (GSH) and
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ascorbic acid were decreased in lymphoma-bearing mice after oral treatment with 50mg/kg of
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body weight per day of crude methanol extract of C. asiatica for 14 days (Jayashree et al., 2003).
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Administration of aqueous extracts of C. asiatica showed to counteract lead-induced oxidative
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stress male rats (Sainath et al., 2011). Flavonoid compounds were present in aqueous extract of
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C. asiatica, showed highest antioxidant property (Pittella et al., 2009). The antioxidant properties
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of essential oils and various extracts of this plant may be a great interest in food industry, since
123
their possible use as natural additives. To study the antioxidant properties and phenolic
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compounds present in C. asiatica, the optimum brewing procedure was studied to use as herbal
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teas (Ariffin et al., 2011).
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Antiulcer activity: C. asiatica showed significant protection against ethanol, aspirin, cold
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restraint stress and pyloric ligation induced gastric ulcers in rats when 200 and 600mg/kg of
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body weight of fresh juice was given orally twice daily for five days (Sairam et al., 2001). Water
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extract of C. asiatica containing asiaticoside were found to reduce the size of the acetic acid
130
induced gastric ulcers in rats (Guo et al., 2004).
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Anxiolytic activity: 12g oral single dose of C. asiatica after 60 minutes significantly attenuated
132
the acoustic startle response (ASR) in human (Bradwejn et al., 2000). The elevated plus maze
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(EPM) test for 5 minutes revealed that administration of standardized extract, methanol and ethyl
134
acetate extracts as well as pure asiaticoside had imparted anxiolytic activity in rats (Wijeweera et
135
al., 2006; Wanasuntronwong et al., 2012). Medication of 500 mg/capsule (concentrated
136
lyophilized of 70% hydro-ethanolic extract of C. asiatica), twice daily, after meal for 60 days in
137
33 patient (18 male and 15 female; average age 33 years) in Kolkata (India) demonstrated that C.
138
asiatica not only significantly had attenuated anxiety related disorders but it also significantly
139
had reduced stress phenomenon and its correlated depression (Jana et al., 2010).
140
Cardioprotective activity: Administration of alcoholic extract of C. asiatica at a dose of
141
1000mg/kg of body weight in Laboratory bred Sprague–Dawley rats significantly reduced the
142
necrosis of the myocardium (Pragada et al., 2004). C. asiatica extract demonstrated the
143
cardioprotective effect at a dose of 200 mg/kg of body weight in adult male albino rats of Wistar
144
strain on antioxidant tissue defense system during adriamycin induced cardiac damage
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(Gnanapragasam et al., 2004). Madecassoside showed protective effect on myocardial ischemia-
146
reperfusion injury in rabbits and rats (Li et al., 2007; Bian et al., 2008).
147
Hepatoprotective activity: Total glucosides extract of C. asiatica showed significant anti-liver
148
fibrosis effect in dimethylnitrosamine induced liver fibrosis in rats (Ming et al., 2004).
149
Asiaticoside revealed hepatoprotective effect against acute liver injury induced by
150
lipopolysaccharide/D-galactosamine in mice (Zhang et al., 2010).
151
Effect on Skin: Asiaticoside stimulated skin aging inhibitor type 1 collagen synthesis in human
152
dermal fibroblast cells and potential use in the treatment and/or prevention of hypertrophic scars
153
and keloids was recommended (Lee et al., 2006; Tang et al., 2011b). Alcoholic extract of C.
154
asiatica showed useful effects in pruritis and other skin disease (Gohil et al., 2010).
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Hydroalcoholic extract of C. asiatica was used to be made herbal creams along with four
156
medicinal plants (Curcuma caesia, Areca catechu, Cinnamon zeylanicum and Tamarindus
157
indica) which showed increased skin hydration, sebum levels, viscoelasticity, and decreased
158
melanin content (Saraf et al., 2012). Asiaticoside promotes skin cell behaviours involved in
159
wound healing by increasing migration rates of skin cells, enhancing the initial skin cell
11
160
adhesion, inducing an increase in the number of normal human dermal fibroblasts (Lee et al.,
161
2012). Aqueous extract of C. asiatica was nano-encapsulated with gelatin and efficiently reduced
162
the expression of matrix metalloproteinase (MMP)-1 in UV-irradiated cells and inhibited
163
hyaluronidase expression in mouse skin (Kwon et al., 2012).
164
Immunomodulating activity: Triterpenoid saponins of C. asiatica showed immunomodulatory
165
effect (Plohmann et al., 1997). Methanolic extract of C. asiatica dramatically increased
166
phagocytic index and total WBC in Swiss Albino mice (Jayathirtha and Mishra, 2004).
167
Administration of water extract of C. asiatica significantly increased proliferation and the
168
production of IL-2 and TNF-α in human peripheral blood mononuclear cells (PBMCs) but
169
ethanol extract had inhibitory effect (Punturee et al., 2005). Asiatic acid and C. asiatica ethanol
170
and dichloromethane extracts showed inhibitory effect on three major cDNA, which expressed
171
human cytochrome P450 (CYP2C9, CYP2D6 and CYP3A4) isoforms (Pan et al., 2010).
172
Radioprotective activity: Aqueous extract C. asiatica showed more radioprotective effect than
173
standard drug “ondansetron” against conditioned taste aversion (behavioural perturbation)
174
induced by 60Co-γ irradiation at low dose 2Gy in male rats (Shobi and Goel, 2001).
175
Administration of 100mg/kg of body weight of aqueous extract of C. asiatica, just 1 hour before
176
irradiation with 8Gy 60Co- γ rays was found most radioprotective in Swiss Albino Mouse
177
(Sharma and Sharma, 2002) and further study revealed that 100mg/kg of body weight of dried
178
powdered extract of C. asiatica had found to be effective against modified 60Co-γ irradiation
179
induced damage in the mouse liver (Sharma and Sharma, 2005). 70% ethanolic extract of C.
180
asiatica significantly reduced radiation-induced damage to DNA (Joy and Nair, 2009).
181
microRNA (miRNA) expression profiling analysis was used to evaluate the protective effects of
182
C. asiatica against Ultraviolet B damage in human keratinocytes, disclosed that miRNAs with
183
altered expression were functionally related with cell proliferation and inhibition of apoptosis,
184
may prevent the skin damage (An et al., 2012).
185
Wound healing activity: A large number of reports have been found about the wound healing
186
activity of C. asiatica (Temrangsee et al., 2011). Aqueous extract of C. asiatica was used to
187
formulate ointment, cream and gel, which evaluate for wound healing in rats showed faster
188
epithelialisation and higher rate of wound contraction(Sunilkumar et al., 1998). Dexamethasone
12
189
suppressed wound in Wistar Albino rats could be healed by ethanolic leaf extracts as like as
190
normal model (Shetty et al., 2006). In a recent study in 200 diabetic patients revealed positive
191
result with C. asiatica extracted capsule without any adverse effect in the department of Surgery,
192
Thammasat University Hospital (Paocharoen, 2010). Wound healing activity of asiaticoside was
193
also reported in guinea pig model at dose 1 mg/kg of body weight and in the chick
194
chorioallantoic membrane model at concentration 40 µg/disk (Shukla et al., 1999). The effects of
195
asiaticoside in human periodontal ligament cells (HPDLs) proliferation, protein synthesis, and
196
osteogenic differentiation were investigated and showed enhanced periodontal tissue healing
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(Nowwarote et al., 2012). At low concentrations aqueous extract of C. asiatica promote
198
epithelium wound healing in rabbit corneal epithelial (RCE) cells (Ruszymah et al., 2012). Ultra-
199
fine cellulose acetate fiber mats containing asiaticoside (in crude extract or pure substance) were
200
prepared and evaluated for wound dressings and loaded herbal substances were found stable up
201
to 4 months, promotes proliferation and upregulating the production of collagen of the seeded
202
(Suwantong et al., 2010). The clinical efficacy and side effects of the oral C. asiatica extract
203
capsule in the diabetic wound healing was investigated (Paocharoen, 2010). Madecassoside
204
showed enhance wound-healing and diminish keloid formation in primary keloid-derived
205
fibroblasts, originating from human earlobe keloids (Song et al., 2012).
206
Memory enhancing Activity: Since the ancient time, C. asiatica is used to enhance intelligence
207
and improve cognitive function. Oral administration with 200 mg/kg of body weight aqueous
208
extract during postnatal development stage increased brain function in juvenile and young adult
209
mice (Rao et al., 2005). Enhanced working memory and improved self-rated mood were
210
observed in 28 patients after higher dose administration of C. asiatiac extract preparations
211
(Wattanathorn et al., 2008). Asiatic acids isolated from C. asiatica showed enhancing learning
212
and memory properties in male Spraque–Dawley rats (Nasir et al., 2011b).
213
Burns: C. asiatica extract and its active constituents are very effective against burns caused by
214
boiling water, electric current or gas exploitation. Combination of C. asiatica extract with an
215
antibiotic was anti-infectious beside healing burns (Salas et al., 2005). Low dose 10−8 to 10−12%
216
(w/w) of asiaticoside application facilitated repairing in mice burned wound (Kimura et al.,
217
2008).
13
218
Anti-psoriatic Activity: C. asiatica shows anti-psoriatic effect on SVK-14 keratinocyte due to the
219
presence of triterpenoid glycosides (Sampson et al., 2001).
220
Antimicrobial Activity: C. asiatica shows antibacterial activity on both Gram positive and Gram
221
negative bacteria. Growth inhibition of Gram positive Bacillus subtilis and Gram negative
222
Pseudomonas aeruginosa, P. cichorii and Escherichia coli was observed in the disc diffusion
223
test of hexane and ethyl acetate extracts of C. asiatica (Escop and Phytotherapy, 2003).
224
1000µg/disc of hot methanolic extract is moderately effective on Staphylococcus aureus and
225
Methicillin Resistant S. aureus (Wild Type) (Zaidan et al., 2005). Micobacterium tuberculosis
226
and M. leprae were reported to be more sensitive to liposomal asiatocoside than free asiatocoside
227
(Fugh-Berman, 2003). Higher antiviral activity was also reported with aqueous extract of C.
228
asiatica against type 2 Herpes simplex virus (Escop and Phytotherapy, 2003).
229
Lervicidal Activity: Haemaphysalis bispinosa (the adult cattle tick), Paramphistomum cervi
230
(sheep fluke), Anopheles subpictus and Culex tritaeniorhynchus showed sensitivity to hexane,
231
chloroform, ethyl acetate, acetone, methanol extract of C. asiatica but methanol extract was the
232
most effective on P. cervi and A. subpictus (Bagavan et al., 2009). 3-O-[a-L-arabinopyranosyl] 2
233
a, 3 ß, 6 ß, 23-a tetrahydroxyurs-12-ene-28-oic acid, a triterpenoid glycoside, exhibited
234
inhibitory activity against larvae of Spilarctia oblique (Shukla et al., 2000).
235
Anti-hyperglycemic effect: Oral administration of asiatic acid and glibenclamide to
236
streptozotocin induced diabetic rats for 45 days prevented the altered activities of key enzymes
237
(glucose-6-phosphatase and fructose-1,6-bisphosphatase) related with hyperglycemia
238
(Ramachandran and Saravanan, 2012).
239
Neuroprotective Activity: Aqueous extract showed neuroprotective effect by increasing the
240
antioxidant enzyme level in mice corpus striatum and hippocampus (Haleagrahara and
241
Ponnusamy, 2010). Fresh leaf extract of C. asiatica was investigated on dendritic morphology of
242
amygdaloid neurons on adult rats, one of the regions concerned with learning and memory,
243
showed a significant increase in the dendritic length and branching points (Rao et al., 2012).
244
Water extract of C. asiatica inhibit the activity of subtypes of phospholipase A2 (PLA2), which
245
is related with neurodegenerative disease (Defillipo et al., 2012). n-hexane, chloroform, ethyl
246
acetate, n-butanol extract of C. asiatica showed anticonvulsant and neuroprotective activity in
14
247
male albino rats (Visweswari et al., 2010). D-galactose induced oxidative and mitochondrial
248
dysfunction and cognitive impairment in mice, which could be significantly improved in six
249
weeks by administration of C. asiatica (150 and 300 mg/kg of body weight) (Kumar et al.,
250
2011). Chronic aluminum exposure in rat induce cognitive dysfunction, apoptosis, oxidative
251
stress and mitochondrial enzyme alteration and administration of C. asiatica found significantly
252
decreased aluminum concentration, improved memory performance, oxidative defense,
253
acetylcholinestrease activity, caspase-3 and reversal of mitochondrial enzyme activity as
254
compared to control (Prakash and Kumar, 2012). The psychoactive and antioxidant role of
255
ethanolic extract of C. asiatica in middle cerebral artery occlusion (MCAO) in rats was
256
evaluated and revealed that administration of C. asiatica extract restored histological
257
morphology of brain, diminished infarction volume, greatly improved the neurobehavioral
258
activity (Tabassum et al., 2012).
259
Asiatic acid possess neuroprotective effects in vitro and in vivo (Xu et al., 2012b), nootropic
260
activity with therapeutic implications for patients with memory loss (Shinomol et al., 2011).
261
Increased dendritic length and branches was observed in rat after fresh leaves extract
262
administration (Mohandas Rao et al., 2006). Three derivatives of asiatic acid were significantly
263
effective in protecting excess glutamate exposed neurons on cultured cortical cells (Lee et al.,
264
2000; Xu et al., 2012b). Non-polar fraction of ethanolic extract containing asiatic acid which
265
found to be increased in neurite outgrowth in human SH-SY5Y cells in the presence of nerve
266
growth factor and administration of ethanolic extract through drinking water demonstrated
267
axonal regeneration in Male Sprague-Dawley rats (Soumyanath et al., 2005). Asiatic acid was
268
reported for the treatment of cerebral ischemia in mice (Krishnamurthy et al., 2009). Asiatic acid
269
showed potential neuroprotective activity against C2-ceramides-induced cell death in primary
270
cultured rat cortical neuronal cells (Zhang et al., 2012) and asiaticoside significantly attenuated
271
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induce Parkinsonism in rat model (Xu et
272
al., 2012a). Asiaticoside was recommended for epilepsy, stroke, multiple sclerosis and other
273
neuropsychiatric disorders (Barbosa et al., 2008).
274
Venous insufficiency Activity: Patients suffering from venous hypertension were positively
275
effective to an oral preparation of total triterpenic fraction of C. asiatica (TTFCA) in the
276
improvement of microcirculation and edema (leg volume) in venous microangiopathy (Cesarone
15
277
et al., 2001). C. asiatica exract regulated mucopolysachharide metabolism in connective tissue in
278
patient with varicose veins (Arpaia et al., 1990). However, a large number of similar studies
279
were reported on venous insufficiency.
280
Others: Asiaticoside was revealed as protective against cecal ligation and puncture (CLP)
281
induced lung injury in mice (Zhang et al., 2010). This plant also increases vigority (Mato et al.,
282
2011). C. asiatica extract in combination with Punica granatum significantly improved clinical
283
signs of chronic periodontitis in 15 patients (Sastravaha et al., 2005). Whole gene expression level
284
were analyzed using microarrays in human dermal fibroblasts (HDFs) to determine whether
285
H2O2 -induced senescence is affected by C. asiatica extracts to characterized the activity of
286
extract in stress-induced premature senescence (SIPS) and found that 39 mRNAs are expressed
287
differentially includes genes that regulate cell growth, apoptosis, DNA replication, transcription,
288
gene silencing, senescence and the spindle checkpoint (Kim et al., 2011). Oral administration of
289
water extract of C. asiatica protected the toxicity induced by exogenously added and
290
endogenously generated β-amyloid in the Tg2576 mouse, which is a murine model of
291
Alzheimer’s disease with high β-amyloid burden in SH-SY5Y cells and MC65 human
292
neuroblastoma cells from (Soumyanath et al., 2012).
293
Contradictions: Clinical study in patients suffering from jaundice showed that all patients had
294
improved with C. asiatica discontinuation and deteriorated after retaking due to having
295
hepatotoxic effect (Jorge and Jorge, 2005). This plant is not applicable for children, pregnant and
296
lactated women (Koh et al., 2009).
297
Traditional uses
298
Traditionally C. asiatica is used to treat differents aliments in different countries for over a long
299
time. Traditional uses of C. asiatica are summarized in table 3.
300
Table 3: Traditional uses of C. asiatica in different regions for different purposes
Regions
Traditional Uses
References
Brazil
Elephantiasis, uterine cancer, leprosy
(Leonard,
2006)
China
Bleeding, scabies and tinea / ringworm, skin ulcers, rash, and redness, abdominal
(Leonard,
pain, diarrhea, dysentery, vomiting, red eyes, swollen throat, tonsillitis,
2006; Koh
16
nosebleeds, jaundice, infectious hepatitis, boils, fistulas, furuncles and carbuncles
et al., 2009)
with toxic swelling, fever, trauma, falls, contusion, fractures, childhood tidal
fevers, measles, asthma, bronchitis, respiratory problems, tuberculosis, pleurisy,
urinary difficulty with stones or bleeding, arsenic poisoning, fear of cold,
dizziness, leprosy, scrofula, improve of appetite, digestion
Europe
Varicose veins
(Leonard,
2006)
Fiji
Skin ulcers, rash, and redness, pimples, stomachache, bleeding ulcer, constipation,
(Leonard,
hemorroids, eye problems, fractures, painful and swollen joints, rib pain, hildhood
2006)
convulsions, post partum weakness, unwanted pregnancy
Hawai'i
India
Indonesia
Blotchy skin, cold extremities, white fingers, poor memory, impotence due to
(Leonard,
vascular disease,
2006)
Eczema, skin ulcers, rash, and redness, abscesses, peptic ulcer, cataract, eye
(Leonard,
problems, fever, cholera, abdominal tumor, anxiety neurosis, insanity, poor
2006; Koh
memory, general debility, blood disease
et al., 2009)
Wounds, colic
(Koh et al.,
2009)
Malagasy
Leprosy
(Leonard,
2006)
Malaya
Dermatosis
(Leonard,
2006)
Mauritius
Cancer
(Leonard,
2006)
Nepal
Indigestion, rheumatism, poor memory, syphilis, general debility, leprosy
(Leonard,
2006)
Philippines
Dysentery, headache, fever, wounds
(Leonard,
2006)
Samoa
Tonga
Turkey
Eye problems, migraines, boils, fistulas, furuncles and carbuncles with toxic
(Leonard,
swelling, venereal disease, leprosy
2006)
Juiced for eye ailments and nasally for migraines, convulsions, delayed closure of
(Leonard,
the fonatel, navel infection in babies
2006)
Spasms, leprosy
(Leonard,
2006)
301
302
In vitro propagation
17
303
Optimum shoots development of C. asiatica were achieved in Duchefa medium supplemented
304
with 2 mg/L 6 benzylaminopurine (BAP) and 0.1 mg/L 1-naphthaleneacetic acid (NAA)
305
(Moghaddam et al., 2011), Murashige and Skoog medium supplemented with 2.5 mg/l kinetin
306
(Prasad et al., 2012). Rooting can be done on full-strength MS medium containing 0.5 mg/L
307
indole-3-butyric acid (IBA) (Moghaddam et al., 2011). Varying level of asiaticoside content in
308
shoot could be achieved with the varying ratio of NH4+-N:NO3--N or Cu2+ concentration in the
309
medium (Prasad et al., 2012).
310
Conclusion
311
Since the time of immemorial C. asiatica is being used for the treatment of wide range of
312
maladies. So far, the reports on bioactivity and clinical trials in different models and human
313
concern the asiaticoside and its derivatives. Recent studies have confirmed the efficacy of this
314
plant and its constituents and extracts to injury, leprosy, tuberculosis, cancer, aging,
315
gastrointestinal disease, skin disease, neurological disorder, cardiovascular problems, ulcer,
316
radiation, respiratory problems and so on. However, further clinical research are essential which
317
can establish the C. asiatica as a potential source of standard drugs.
318
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319
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320
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321
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322
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325
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326
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327
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328
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389
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402
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407
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408
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410
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416
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421
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422
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423
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424
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425
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431
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432
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433
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436
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437
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438
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439
Asiaticoside induces human collagen I synthesis through TGFbeta receptor I kinase (TbetaRI kinase)-independent
440
Smad signaling. Planta Medica 72, 324–328.
22
441
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442
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443
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444
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445
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446
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447
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448
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449
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450
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451
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452
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